PROJECT SUMMARY/ABSTRACT: The overarching goal of this application is to identify human placental trophoblast-associated pathways that alter maternal-fetal sensitivity to teratogenic virus infections. The hematogenous spread of viruses from the maternal host to the fetal compartment can induce devastating consequences in the developing embryo. Even in the absence of vertical transmission, viral infections can compromise maternal health and jeopardize pregnancy outcome. Located in direct contact with maternal blood, placental trophoblasts actively communicate factors that might both protect against or sensitize maternal and fetal tissues to viral infections. The proposed research combines expertise in virology, immunology, and placental biology to identify placental-derived intrinsic and extrinsic pathways that bolster or weaken antiviral defenses in a cell-type specific manner. We have previously identified two pathways employed by placental trophoblasts to restrict viral infections. These include the constitutive release of small RNAs (microRNAs) in vesicles and antiviral type III interferons (IFNs). These previous studies suggest that trophoblasts form a barrier to the vertical transmission of viruses and that viruses associated with fetal disease must bypass trophoblast-intrinsic antiviral pathways to be transmitted by the hematogenous route. In this application, we will identify cell intrinsic IFN-mediated effectors that mediate placental resistance to infection to a panel of teratogenic viruses including ZIKV, Rubella virus (RuV), human cytomegalovirus (CMV), and herpesviruses (HSV-1 and HSV-2). In addition, we will identify effectors secreted from human trophoblasts that sensitize monocytes to viral infections and determine whether these factors act on other teratogenic viruses and on other immune cell populations We have identified novel pathways for transmissible placental resistance to viral infections and enhanced susceptibility to viral infections. In deciphering the underlying mechanisms that constitute these pathways, we may illuminate the basis of trophoblast resistance to viruses and identify cell populations that may be particularly sensitive to viral infections during pregnancy. These studies could inform the development of innovative therapeutics designed to mitigate and/or prevent viral infections, thus reducing the burden of infection related feto-maternal morbidity and mortality.